Process for preparation of fused pyrroles

ABSTRACT

The invention provides processes for the preparation of fused pyrroles, preferably indoles, which permit the use of inexpensive aromatic amines themselves as the raw material and attain high atomic efficiency and high regioselectivity. Specifically, a process for the preparation of fused pyrroles, e.g., indoles bearing methyl at the 3-position of pyrrole ring and R 1  (or R 2 ) of the general formula (4) at the 2-position thereof, or 3,3-disubstituted indoles bearing R 1  and R 2  at the 3-position of pyrrole ring and methyl at the 2-position thereof, characterized by reacting an alkynol of the general formula (4) with an aromatic primary amine in the presence of a ruthenium complex, more preferably with an acid or an ammonium salt thereof being made to coexist.  
                 
 
     [In the general formula (4), R 1  and R 2  are each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or alternatively R 1  and R 2  may be united to form an alkylene chain.]

TECHNICAL FIELD

[0001] This invention relates to a novel process for producing condensedpyrroles useful as starting materials, intermediates etc. for dyes,perfumes etc. or as starting materials for synthesizing physiologicallyactive substances.

BACKGROUND ART

[0002] There are many physiologically active substances containing acondensed pyrrole ring, and in particular new methods of producingsubstances containing an indole ring have been actively studied from the19th century to the present. Besides the Fischer method known for 100years or more, methods such as Bischler method, Madelung method,Reissert method and a method of using a palladium catalyst have beendeveloped, but have not surpass the Fischer method in general andeconomical aspects.

[0003] The Fischer method is a method of synthesizing a hydrazone froman aryl hydrazine and a ketone and then treating it with an acid to formindole. Because various kinds of ketones are easily available, thismethod is generally usable, but there are problems such as necessity forsynthesis of hydrazine from an aniline derivative and occurrence ofvarious regioisomers at the time of forming an indole ring, etc. Variousattempts have been made on regioselective synthesis, but have neverprovided complete solution (J. Org. Chem., 56, 3001(1991); J. Org.Chem., 58, 7638 (1993), etc.).

[0004] The reaction scheme of synthesizing indole by the Fischer methodis shown below:

[0005] On the other hand, as organometallic chemistry has advanced forabout 30 years, methods of using a palladium catalyst have beenextensively developed. Such methods utilize the cross-coupling reactionunique to the palladium catalyst. These methods involve reactingo-iodoaniline with an alkyne etc. to synthesize o-alkynyl aniline andthen adding an amine to the alkyne in the molecule to form an indolering, and there are a vast number of reports thereon. The disadvantagesof such methods are that o-iodoaniline is considerably more expensivethan aniline; although the atomic weight of iodine is 127 which ishigher than that (92) of the aniline nucleus, the iodine does not remainin the indole skeleton of the product and is discarded as a byproduct,that is, the atom efficiency is low; nitrogen in the aniline shouldpreviously been converted into e.g. amide (Chem. Pharm. Bull., 1305(1988); Tetrahedron Lett., 3915 (1992), etc.).

[0006] The reaction scheme of synthesizing indole by the method of usinga palladium catalyst is shown below:

[0007] Further, as a method of using a ruthenium catalyst, a method ofsynthesizing indole from aniline and 1,2-diol is known. This method issuperior in features such as atom efficiency and usability of anilineitself as a starting material, but there are problems such as formationof a mixture of isomers from asymmetric diol due to generally lowregioselectivity, necessity for relatively high temperature (180° C.),necessity for an argon atmosphere, necessity for a solvent, etc. (J.Org. Chem., 52, 1673 (1987), etc.).

[0008] The reaction scheme of synthesizing indole by the method of usinga ruthenium catalyst is shown below:

DISCLOSURE OF INVENTION

[0009] This invention was made in view of the present circumstancesdescribed above, and the object of this invention is to provide aprocess for producing condensed pyrroles having high regioselectivity,preferably indoles, which achieves high atom efficiency and can utilizeinexpensive aromatic amines itself as the starting material.

BEST MODE FOR CARRYING OUT THE INVENTION

[0010] This invention relates to a process for producing condensedpyrroles, which comprises allowing an alkyne alcohol represented byformula (4):

[0011] wherein R¹ and R² independently represent a hydrogen atom, analkyl group which may have a substituent group or an aryl group whichmay have a substituent group, and R¹ and R² are combined to form analkylene chain, to react with an aromatic primary amine in the presenceof a ruthenium complex.

[0012] For example, the compounds obtained by the process of thisinvention include:

[0013] the compound represented by the general formula (1) (referred tohereinafter as Compound (1)):

[0014] wherein double-circled Ar represents an aromatic ring, R¹ (or R²)represents a hydrogen atom, an alkyl group which may have a substituentgroup or an aryl group which may have a substituent group, and R³represents an alkyl group which may have a substituent group, an arylgroup, a hydroxy group, an alkoxy group, an amide group, a ketone group,an ester group or a halogeno group;

[0015] the compound represented by the general formula (2) (referred tohereinafter as Compound (2)):

[0016] wherein double-circled Ar represents an aromatic ring, R¹ (or R²)represents a hydrogen atom, an alkyl group which may have a substituentgroup or an aryl group which may have a substituent group, and R³represents an alkyl group which may have a substituent group, an arylgroup, a hydroxy group, an alkoxy group, an amide group, a ketone group,an ester group or a halogeno group; and

[0017] the compound represented by the general formula (3) (referred tohereinafter as Compound (3)):

[0018] wherein double-circled Ar represents an aromatic ring, R³represents an alkyl group which may have a substituent group, an arylgroup, a hydroxy group, an alkoxy group, an amide group, a ketone group,an ester group or a halogeno group, and R¹ and R² have the same meaningsas defined above.

[0019] In the general formula (4), when R¹ and/or R² is a hydrogen atom,the product is Compound (1) and/or (2), and when both R¹ and R² areother than hydrogen atom, the product is Compound (3).

[0020] In the alkyne alcohols represented by the general formula (4)used in the invention, the alkyl group in the optionally substitutedalkyl group represented by R¹ and R² includes e.g. a C₁₋₂₀ linear orbranched alkyl group such as methyl group, ethyl group, propyl group,butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonylgroup, decyl group, dodecyl group, pentadecyl group, hexadecyl group,octadecyl group, nonadecyl group and eicosyl group. The aryl group inthe optionally substituted aryl group includes e.g. a phenyl group,tolyl group, xylyl group, naphthyl group, methyl naphthyl group,biphenyl group etc. The substituent groups on these alkyl and arylgroups include e.g. an alkoxy group such as methoxy group and ethoxygroup, an alkenyl group such as vinyl group and allyl group, a halogenogroup such as chloro group, bromo group and fluoro group, and an amidegroup, an ester group etc.

[0021] When R¹ and R² are combined to form an alkylene chain, thesegroups together with their adjacent C atom form e.g. a cyclopropanering, cyclopentane ring, cyclohexane ring etc.

[0022] The aromatic primary amines used in the invention include e.g.aniline and nucleus-substituted derivatives thereof, 1- or 2-naphthylamine and nucleus-substituted derivatives thereof, 1- or2-aminoanthracene and nucleus-substituted derivatives thereof, and2-aminobiphenyl and nucleus-substituted derivatives thereof.

[0023] In the formulae (1), (2) and (3), the double-circled Arrepresents an aromatic ring, and the aromatic ring referred to hereinmay be a monocyclic, condensed polycyclic, non-condensed polycycliccarbon ring or heterocyclic ring, and includes e.g. a benzene ring,naphthalene ring, anthracene ring, phenanthrene ring, biphenyl,terphenyl, pyridine ring, pyrimidine ring etc. The heterocyclic ring ispreferably a ring having 1 to 3 heteroatoms such as O, S and N.

[0024] The alkyl group in the optionally substituted alkyl grouprepresented by R³, that is, a substituent group on the aromatic ringmentioned above, includes e.g. a C₁₋₆ linear or branched lower alkylgroup such as methyl group, ethyl group, propyl group, butyl group,pentyl group and hexyl group, and the substituent group thereon includesa hydroxyl group, an alkoxy group such as methoxy group, ethoxy group,n-propoxy group and isopropoxy group, and a halogen atom such aschlorine, bromine and fluorine.

[0025] The aryl group represented by R³ includes e.g. a phenyl group,tolyl group, xylyl group, naphthyl group, methyl naphthyl group,biphenyl group etc., and the alkoxy group represented by R³ includese.g. a methoxy group, ethoxy group, n-propoxy group, isopropoxy group,n-butoxy group, t-butoxy group etc., and the halogeno group representedby R³ includes e.g. a chloro group, bromo group, fluoro group etc.

[0026] In addition to those described above, other substituent groupsrepresented by R³ on the aromatic ring include a hydroxy group, amidegroup, ketone ring, ester group etc.

[0027] Among the aromatic primary amines having these substituentgroups, those aromatic primary amines having electron-donatingsubstituent groups such as hydroxy group and alkoxy group areparticularly highly reactive, thus giving high yield.

[0028] The ruthenium complex used in the process of this invention maybe any complex capable of demonstrating a catalytic action in reactionof the alkyne alcohol with the aromatic primary amine, and for example,use can be made of ruthenium complexes used in conventional processesfor producing an imine and enamine by adding e.g. an amine to a terminalalkyne.

[0029] The ruthenium complexes usable in this invention include e.g.Ru₃(CO)₁₂, Ru(CO)₃(C₈H₁₂), Ru(CO)₃(C₈H₈), [RuCl₂(CO₃)]₂,[Ru(C₅H₅)(CO)₂]₂, (C₂H₅)₄N.[HRu₃(CO)₁₂], HRu₄(CO)₁₂,[(C₂H₅)₄N]₂.[Ru₆C(CO)₁₆], [(Ph₃P)₂N]₂.[Ru₆(CO)₁₈],[(Ph₃P)₂N]₂.[Ru₁₀C(CO)₂₄], [RuCl₂(C₆H₆)]₂, RuCl₃.3H₂O, [RuCl₂(PPh₃)₃],[RuCl₂(C₆H₆)(PPh₃)], [RuCl₂(C₆H₆)(PBu₃)], RuCl₂(C₆H₆)(P(C₆F₅)₃), etc. Inthese formulae, Ph represents a phenyl group, and Bu represents a butylgroup.

[0030] The ruthenium complex is particularly preferably Ru₃(CO)₁₂. Theamount of the ruthenium complex added to the reaction system is usually0.1 to 10 mol-%.

[0031] The process of this invention is conducted preferably in thecoexistence of an acid or an ammonium salt thereof (referred tohereinafter as “additive”).

[0032] Depending on the type of the aromatic primary amine used as thestarting material, the amount of the additive is not necessarily thesame, but generally speaking, when e.g. Ru₃(CO)₁₂ is used as theruthenium complex, the additive is used in an amount of about 3equivalents relative to Ru₃(CO)₁₂ (that is, in an amount of about 1equivalent relative to the ruthenium atom), whereby the compoundsrepresented by the following general formula (5):

[0033] (wherein the double-circled Ar, R¹, R² and R³ have the samemeanings as defined above) are obtained, while the additive is used inexcess, for example in an amount of 10 equivalents or more relative toRu₃(CO)₁₂ (that is, in an amount of 3 equivalents or more relative tothe ruthenium atom), the desired condensed pyrroles can be obtained.That is, the additive promotes both the first and second reactions. Asmall amount of the additive suffices for the first reaction, but arelatively large amount thereof is necessary for the second reaction.When the additive is used in an amount of 3 to 30 equivalents relativeto Ru₃(CO)₁₂ (that is, in an amount of 1 to 10 equivalents relative tothe ruthenium atom), the product is considered to occur as a mixture ofthe condensed pyrrole and an intermediate thereof, but formation of theproduct depends on the type of the aromatic primary amine used. This isbecause there is the case where even if the amount of the additive islow, the pyrrole ring is also formed depending on the type of thearomatic primary amine used (for example, m-hydroxy aniline can beeasily cyclized to form indole in high yield even if the amount of theadditive is 3 equivalents relative to Ru₃(CO)₁₂ (1 equivalent relativeto the ruthenium atom).

[0034] Depending on the reaction conditions, the process of thisinvention can make use of a 2-stage reaction process wherein thecompound represented by the general formula (5) above is first obtainedfrom the alkyne alcohol and the aromatic primary amine, and thenconverted into the desired condensed pyrrole, or a process wherein thealkyne alcohol and the aromatic primary amine are converted directlyinto the condensed pyrrole. In the case of the 2-stage synthesis, thecompound represented by the general formula (5) may be isolated once, orwithout isolation, the reaction mixture may be used as such in thesecond reaction. When the intermediate is isolated, further addition ofthe ruthenium complex and the additive is naturally necessary forconducting the next reaction, but when the reaction mixture is subjectedas such without isolation to the second reaction, it is enough to add adeficient amount of the additive.

[0035] As the additive, almost all acids and ammonium salts thereof areeffective. Generally, stronger acidic additives tend to be highlyeffective, however among hydrohalogenic acids, HF and its ammonium saltare the most effective. Specifically, the acids include e.g. HPF₆, HBF₄,BF₃, CF₃SO₃H, CH₃SO₃H, C₆H₆SO₃H, CH₃C₆H₆SO₃H, H₂SO₄, HI, HBr, HCl, HF,CF₃COOH, ClCH₂COOH, CH₃COOH, C₆H₅COOH etc., and effective ammonium saltsare those except for quaternary ones (N(CH₃)₄ ⁺ etc.). That is,unsubstituted ammonium salts (NH₄+ salts), primary ammonium salts (forexample C₆H₅NH₃ ⁺ salt etc.), secondary ammonium salts (for exampleNH₂(C₂H₅)₂ ⁺ salt etc.), tertiary ammonium salts (for example NH(C₂H₅)₃⁺ salt etc.) have the same effect.

[0036] Usually, the additive preferably used is a salt consisting of thearomatic primary amine used in the reaction and one of the above acids.

[0037] The reaction is conducted usually under heating at 80 to 200° C.Replacement of the atmosphere in the reaction system by e.g. nitrogen orargon is not particularly necessary.

[0038] This reaction does not particularly necessitate the presence of asolvent, but can also be conducted using a general organic solvent.Preferable examples of the solvent includes those having a boiling pointof 80° C. or more, such as ethylene glycol, grime, digrime, toluene,benzene, xylene, 2-propanol, 1,4-dioxane, dimethylformamide and dimethylsulfoxide.

[0039] The method of isolating the condensed pyrrole as the finalproduct can be conducted using an extraction procedure. That is, anexcess of the aromatic primary amine etc. can be removed by adding anextraction solvent such as diethyl ether, dichloromethane and toluene tothe reaction solution and then washing the product several times withe.g. 1 M hydrochloric acid. In this procedure, the product can usuallyattain 90 to 99% purity. The product can be further purified byre-crystallization, distillation etc.

[0040] In the process of this invention, when a primary or secondaryalcohol is used as the starting alkyne alcohol, that is, when thealkylene alcohol of the general formula (4) wherein R¹ and/or R² is ahydrogen atom is used, Compound (1) is obtained as the major finalproduct.

[0041] Compound (1) has a methyl group as a substituent group at the3-position of the pyrrole ring and R¹ (or R²) as a substituent group atthe 2-position. Although Compound (2) wherein the substituent groups atthe 2- and 3-positions have been replaced with each other is alsosimultaneously formed in a smaller amount, Compound (1) can be obtainedas the major product. Compound (1): Compound (2) is usually at least9:1.

[0042] In the process of this invention, when a tertiary alcohol is usedas the starting alkyne alcohol, that is, when the alkylene alcohol ofthe general formula (4) wherein both R¹ and R² are other than hydrogenatom is used, Compound (3) i.e. a 3,3-di-substituted compound having R¹and R² as substituent groups at the 3-position of the pyrrole ring and amethyl group at the 2-position is obtained as the final product.

[0043] The reaction scheme of the process of this invention is shownbelow by reference to an example wherein an aniline derivative is usedas the aromatic primary amine.

[0044] (A) When the alkyne alcohol used is the alkyne alcohol of thegeneral formula (4) wherein R² is a hydrogen atom

[0045] (B) When the alkyne alcohol used is the alkyne alcohol of thegeneral formula (4) wherein both R¹ and R² are other than hydrogen atom

EXAMPLES

[0046] Hereinafter, this invention is described in more detail byreference to the Examples, which however are not intended to limit thisinvention.

[0047] Confirmation of the products in the Examples below was conductedby ¹H NMR and GC-MS.

Example 1 Synthesis of 2,3-dimethyl indole by using a Ru₃(CO)₁₂ catalyst

[0048] 3-Butine-2-ol (0.701 g, 10 mmol), aniline (0.931 g, 10 mmol),Ru₃(CO)₁₂ (32.0 mg, 0.05 mmol) and aniline hydrochloride (0.259 g, 2.0mmol) were placed in a 10 ml round-bottomed flask, and the mixture wasstirred at 120° C. for 12 hours. After cooling, dichloromethane (3 mL)was added, and the organic layer was washed twice with 1 M hydrochloricacid (2 mL) and once with water (2 mL). The organic layer was dried oversodium sulfate, and the solvent was distilled away, whereby 2,3-dimethylindole (1.31 g; 9.0 mmol; yield, 90%; purity, about 99%) was obtained.

Example 2 Synthesis of 3-methyl-2-pentyl indole by using a Ru₃(CO)₁₂catalyst

[0049] 1-Octyne-3-ol (1.136 g, 9 mmol), aniline (0.559 g, 6 mmol),Ru₃(CO)₁₂ (16.0 mg, 0.025 mmol) and aniline hydrochloride (0.130 g, 1.0mmol) were placed in a 10 ml round-bottomed flask, and the mixture wasstirred at 140° C. for 9 hours. After cooling, diethyl ether (3 mL) wasadded, and the organic layer was washed twice with 1 M hydrochloric acid(2 mL) and once with water (2 mL). The organic layer was dried oversodium sulfate, and the solvent was distilled away, whereby an 11:1mixture of 3-methyl-2-pentyl indole and 2-methyl-3-pentyl indole (1.262g; 6.3 mmol; yield, 95%; purity, about 95% or more) was obtained.

Example 3 Synthesis of 2-ethyl-3-methyl indole by using a Ru₃(CO)₁₂catalyst

[0050] 1-Pentine-3-ol (0.757 g, 9 mmol), aniline (0.559 g, 6 mmol),Ru₃(CO)₁₂ (16.0 mg, 0.025 mmol) and aniline hydrochloride (0.130 g, 1.0mmol) were placed in a 10 ml round-bottomed flask, and the mixture wasstirred at 140° C. for 7.5 hours. After cooling, dichloromethane (3 mL)was added, and the organic layer was washed twice with 1 M hydrochloricacid (2 mL) and once with water (2 mL). The organic layer was dried oversodium sulfate, and the solvent was distilled away, whereby a 9.3:1mixture of 2-ethyl-3-methyl indole and 3-ethyl-2-methyl indole (1.06 g;6.67 mmol; yield, 95%) was obtained.

Example 4 Synthesis of 2-methyl-3H-indole-3-spiro-1′-cyclohexane byusing a Ru₃(CO)₁₂ catalyst

[0051] 1-Ethynyl-1-cyclohexanol (1.242 g, 10 mmol), aniline (0.931 g, 10mmol), Ru₃(CO)₁₂ (32.0 mg, 0.05 mmol) and aniline hydrochloride (0.259g, 2.0 mmol) were placed in a 10 ml round-bottomed flask, and themixture was stirred at 120° C. for 12 hours. After cooling,dichloromethane (3 mL) was added, and the organic layer was washed twicewith 1 M hydrochloric acid (2 mL) and once with water (2 mL). Theorganic layer was dried over sodium sulfate, and the solvent wasdistilled away, whereby 2-methyl-3H-indole-3-spiro-1′-cyclohexane (24mg; 0.12 mmol; yield, 1.2%; purity, 95% or more) was obtained.

Examples 5 to 12 Synthesis of Various Indoles by Using a Ru₃(CO)₁₂Catalyst

[0052] In the following reaction scheme, R¹ and R³ were replacedrespectively by various groups shown in Table 1 below, and the reactionwas conducted under the reaction conditions shown in Table 1, followedby post-treatment in accordance with the methods described in Examples 1to 3, to give the results shown in Table 1. TABLE 1

1/Additive/2 Examples R¹ R³ (mmol) Time (h) Yield (%) 3a/3b  5^(c) H Ph6.0/1.0^(a)/9.0  7^(c) >95 1/16   6^(e) m-OH CH₃ 6.0/1.0^(a)/9.0  8^(a)50 —  7^(c) p-CH₃O CH₃ 6.0/1.0^(a)/9.0  8^(c) 89 —  8^(e) 3,4-di-(CH₃O)n-C₃H₇ 5.0/1.0^(a)/7.0 24^(e) 75  9^(c) p-CH₃ C₂H₅ 6.0/1.0^(a)/9.0 9^(c) 97 1/8.4 10^(e) o-CH₃ CH₃ 7.0/0.75^(b)/9.0 17^(e) 91 — 11^(e,f)p-Cl CH₃ 5.0/0.75^(b)/7.0  9^(e) 80 — 12^(e,g) o-CO₂CH₃ CH₃7.0/0.7^(b)/9.0 23^(e) 40 —

Example 13 Synthesis of 2,3-dimethylbenzo[g]indole by Using a Ru₃(CO)₁₂Catalyst

[0053] 3-Butine-2-ol (0.631 g, 9 mmol), 1-napthylamine (0.859 g, 6mmol), Ru₃(CO)₁₂ (16.0 mg, 0.025 mmol), ammonium hexafluorophosphate(0.041 g, 0.25 mmol) and 1 ml ethylene glycol were placed in a 10 mlround-bottomed flask, and the mixture was stirred at 140° C. for 20hours. After cooling, diethyl ether (3 mL) was added, and the organiclayer was washed twice with 1 M hydrochloric acid (2 mL) and once withwater (2 mL). The organic layer was dried over sodium sulfate, and thesolvent was distilled away, whereby 2,3-dimethylbenzo[g]indole (1.113 g;5.7 mmol; yield, 95%; purity, 95% or more) was obtained.

INDUSTRIAL APPLICABILITY

[0054] The advantages of the process of this invention are as follows:

[0055] (i) An inexpensive aromatic amine itself, for example anilineitself can be utilized as the starting material;

[0056] (ii) The regioselectivity in the reaction is so high that theproduct having a methyl group at the 3-position of the pyrrole ring andR¹ (or R²) in the general formula (4) as a substituent group at the2-position can be selectively obtained. [It is known that in the Fischermethod, regio-control is generally difficult, but when 2-alkanone(methyl alkyl ketone) is used, 2-methyl-3-alkyl indole is predominantlyobtained while 3-methyl-2-alkyl indole cannot be obtained. Theoutstanding advantage of this reaction is that 3-methyl-2-alkyl indolewhich cannot be obtained in the Fischer method can be selectivelyobtained.]; and

[0057] (iii) The atom efficiency in the reaction is very high, and asthe reaction proceeds, one molecular of water is merely formed, and thusthe influence of the reaction on the environment is also low.

1. A process for producing condensed pyrroles, which comprises allowingan alkyne alcohol represented by formula (4):

wherein R¹ and R² independently represent a hydrogen atom, an alkylgroup which may have a substituent group or an aryl group which may havea substituent group, and R¹ and R² may be combined to form an alkylenechain, to react with an aromatic primary amine in the presence of aruthenium complex.
 2. The process according to claim 1, wherein thecondensed pyrroles are compounds represented by formula (1):

wherein double-circled Ar represents an aromatic ring, R¹ (or R²)represents a hydrogen atom, an alkyl group which may have a substituentgroup or an aryl group which may have a substituent group, and R³represents an alkyl group which may have a substituent group, an arylgroup, a hydroxy group, an alkoxy group, an amide group, a ketone group,an ester group or a halogeno group.
 3. The process according to claim 1,wherein the condensed pyrroles are compounds represented by formula (2):

wherein double-circled Ar represents an aromatic ring, R¹ (or R²)represents a hydrogen atom, an alkyl group which may have a substituentgroup or an aryl group which may have a substituent group, and R³represents an alkyl group which may have a substituent group, an arylgroup, a hydroxy group, an alkoxy group, an amide group, a ketone group,an ester group or a halogeno group.
 4. The process according to claim 1,wherein the condensed pyrroles are compounds represented by formula (3):

wherein double-circled Ar represents an aromatic ring, R³ represents analkyl group which may have a substituent group, an aryl group, a hydroxygroup, an alkoxy group, an amide group, a ketone group, an ester groupor a halogeno group, and R¹ and R² have the same meanings as definedabove.
 5. The process according to any one of claims 1 to 4, wherein theruthenium complex is Ru₃(CO)₁₂.
 6. The process according to claim 5,wherein Ru₃(CO)₁₂ is used in an amount of 0.1 to 10 mol-%.
 7. Theprocess according to any one of claims 1 to 6, wherein the reaction isconducted in the coexistence of an acid or an ammonium salt thereof. 8.The process according to claim 7, wherein the acid or an ammonium saltthereof is used in an amount of 3 equivalents or more relative toRu₃(CO)₁₂ (1 equivalent or more relative to the ruthenium atom).
 9. Theprocess according to claim 7 or 8, wherein the acid or an ammonium saltthereof is a salt consisting of an acid and the aromatic primary amineused in the reaction.
 10. The process according to any one of claims 1to 9, wherein the reaction is conducted under heating at 80 to 200° C.11. The process according to claim 1, which comprises allowing an alkynealcohol represented by formula (4):

wherein R¹ and R² have the same meanings as defined above, to react withan aromatic primary amine in the presence of a ruthenium salt and in thecoexistence of an acid or an ammonium salt thereof in an amount of 1 to10 equivalents relative to the ruthenium atom, to form a compoundrepresented by formula (5):

wherein double-circled Ar, R¹, R² and R³ have the same meanings asdefined above, then isolating the compound and adding an additionalruthenium complex and an acid or an ammonium salt thereof to react withthe compound, or adding an acid or an ammonium salt thereof to reactwith the compound without isolation in the same system.